This proposal is requesting funds to acquire an Orbitrap Fusion Lumos ETD Mass Spectrometer for the Medical University of South Carolina to support our NIH funded investigators' efforts to discover mechanisms of protein regulation involved in cardiovascular disease, cancer, diabetes, osteoporosis, addiction, and neurological diseases. Currently, investigators are relying on one Orbitrap Elite instrument to characterize the impact of drugs/hormones, genetic alterations, and disease on changes in protein expression, protein interactions, and post-translational modifications. This instrument, purchased in 2012 specifically for the ability to couple multiple fragmentation capabilities with high resolution mass measurements, has been used by over 80 investigators and operates with a growing backlog. To provide our investigators with timely access to instrumentation, meet the growing demand for quantitative experiments, enable additional fragmentation capabilities for the detection of post-translational modifications, while addressing the diverse needs of the user base an Orbitrap Fusion Lumos ETD is requested. This tribrid instrument with ion trap, orbitrap, and quadrupole mass analyzers is faster and exhibits improved selection of precursor ions within a narrow mass range thereby increasing the sensitivity, selectivity, and reproducibility of measurements. For the analysis of post-translationally modified proteins, the instrument has added fragmentation capabilities (hybrid EThcD and high capacity ETD) for more confident site assignment of fragile modifications such as O-GlcNAc modification, detection of redox-sensitive modifications, and characterization of glycopeptides. The requested instrumentation is to be housed in the Mass Spectrometry Facility, a University Research Resource Facility, to provide LC-MS/MS based proteomic capabilities to investigators at the Medical University of South Carolina and the surrounding academic research institutions in South Carolina.